The subthalamic nucleus (STN) is composed of glutamate-containing neurons that drive the output of the basal ganglia. Moreover, the bursting pattern of action potentials in STN neurons has been associated with symptoms of Parkinson's disease. However, there is much to be learned about physiological and pharmacological mechanisms that regulate the activity of STN neurons. Using standard whole-cell patch-clamp recording techniques in slices of rat brain, our preliminary data show that blocking of the ATP-sensitive K+ (K-ATP) channels significantly increases firing rate, prolongs depolarizing plateau potentials, and augments N-methyl-D-aspartate (NMDA)-induced burst firing in STN neurons. Moreover, we present data suggesting that NMDA receptor stimulation produces concomitant activation of K-ATP current by a nitric oxide- dependent mechanism. This effect of NMDA might be specific for STN neurons because NMDA does not evoke K-ATP currents in substantia nigra pars compacta dopamine neurons. The aims of this grant application are to 1) define the receptor pharmacology of K-ATP currents in STN neurons, 2) characterize NMDA/K-ATP interactions on membrane properties, 3) identify second messenger systems that mediate NMDA activation of K-ATP currents, and 4) characterize the influence of K-ATP currents on excitability and firing patterns of STN neurons from normal rats as well as in a 6-hydroxydopamine rat model of Parkinson's disease. Our proposed studies will significantly increase our understanding of how STN neurons are regulated by NMDA receptor- gated and K-ATP currents. Results may also suggest new ways to pharmacologically modify STN neuronal activity that would benefit patients with Parkinson's disease. PUBLIC HEALTH RELEVANCE Many studies suggest that excessive burst firing in subthalamic nucleus (STN) neurons contributes to symptoms of Parkinson's disease. Our preliminary studies show that burst firing that is evoked by N-methyl-D-aspartate (NMDA) receptor stimulation can be inhibited by concomitant activation of inhibitory currents generated by ATP-sensitive K+ (K-ATP) channels. By better understanding the interplay between NMDA and K-ATP currents in the STN, our studies may lead to new pharmacological strategies for the treatment of Parkinson's disease symptoms.